Sodium is the major osmotically active substance in the extracellular fluid, which means wherever sodium goes, water follows. Na⁺ along with Cl⁻, the most abundant anion, determine the extracellular fluid volume.² About 26,000 mEq of Na⁺ passes through the glomerular membrane into the tubular filtrate daily. However, daily Na⁺ intake averages only about 150 mEq.¹ Therefore the kidney’s main job is to reabsorb Na⁺, not to excrete it. Because of the major role of Na⁺ in maintaining fluid balance, the body places a priority on Na⁺ reabsorption, even at the expense of imbalances in other electrolytes. As noted in Chapter 21, greater than 99% of the Na⁺ in the filtrate is reabsorbed. Na⁺ is reabsorbed from the tubular filtrate by two mechanisms: (1) primary active transport and (2) secondary active secretion of H⁺ and K⁺ ions.

Primary Active Transport of Sodium

Primary active transport accounts for most Na⁺ reabsorption from the tubular filtrate and occurs in all tubules except the descending loop of Henle.¹ On the nonluminal side of the tubular epithelial cell (Figure 22-1), the sodium-potassium-adenosine triphosphatase (Na⁺-K⁺-ATPase) pump actively transports Na⁺ ions out of the cell, into the interstitial fluid, and ultimately into the peritubular capillary blood. The membrane protein forming this pump hydrolyzes ATP molecules to generate the energy necessary to actively transport Na⁺ ions out of the cell. K⁺ ions are simultaneously transported into the cell from the interstitial fluid, but more Na⁺ ions are pumped out of the cell than K⁺ ions are pumped in. This process keeps Na⁺ concentration in the tubule cell very low and creates a negatively charged intracellular environment.

Figure 22-1 Na⁺ reabsorption through primary active transport. Na⁺ diffuses from the filtrate and into the tubule cell in response to its concentration gradient and the electrostatic attraction of the cell’s negatively charged interior. The Na⁺-K⁺-ATPase pump helps generate this intracellular negativity by pumping out more Na⁺ than it pumps in K⁺. Cl⁻ passively accompanies Na⁺ (cotransport).

Because [Na⁺] is comparatively much higher in the tubular filtrate, and Na⁺ is a positively charged ion, both chemical diffusion and electrostatic forces favor its movement from the tubular lumen into the cell, down its concentration and electrostatic gradients.¹ Specialized sodium-carrier proteins in the luminal membrane of the tubule cell facilitate this process by binding with Na⁺ ions and releasing them inside of the tubule cell. Cl⁻ ions passively follow Na⁺ ions, which maintains the filtrate’s electrical neutrality. That is, the transport of the positively charged Na⁺ ion out of the filtrate into the tubular cell leaves the tubular lumen negatively charged with respect to the extracellular fluid and the blood; this electrostatic gradient causes Cl⁻ (the most abundant anion in the filtrate) to diffuse passively through paracellular pathways (between the tubule cells) into the interstitial space and ultimately into the capillary blood.¹ Cl⁻ diffusion also occurs because of a concentration gradient; that is, Na⁺ transport out of the filtrate creates an osmotic gradient for water reabsorption from the tubular lumen, which concentrates Cl⁻ ions in the filtrate. Cl⁻ thus passively diffuses out of the filtrate in response to both electrostatic and chemical diffusion forces.¹

The brush border on the luminal side of the epithelial cell provides an extensive surface area for Na⁺ transport. Sodium-carrier proteins in these membranes are also important in secondary active reabsorption, or cotransport.

Secondary Active Secretion of Hydrogen and Potassium

Reabsorption of Na⁺ by way of the active secretion of H⁺ and K⁺ ions is a more complex process. For H⁺ secretion (Figure 22-2), the process proceeds in the following manner: First, carbon dioxide (CO₂) from the peritubular capillary blood diffuses into the tubular cells, where it reacts with water (in the presence of carbonic anhydrase) and forms H⁺ ions. The H⁺ ion in the tubule cell and Na⁺ ion in the filtrate simultaneously combine with opposite ends of a protein-carrier molecule in the luminal border of the cell membrane. Na⁺ diffusion into the cell, down its concentration and electrostatic gradients (described previously), provides the energy for H⁺ transport into the filtrate (see Figure 22-2). This process is called countertransport because the transported ions move in opposite directions. Figure 22-2 shows that the < ?xml:namespace prefix = "mml" />HCO3− ion generated by the reaction between CO₂ and water accompanies Na⁺ transport out of the cell and into the peritubular capillaries. In this way, Na⁺ reabsorption from the filtrate occurs without Cl⁻ reabsorption. A similar countertransport mechanism is involved in the secondary active secretion of K⁺ into the tubules in exchange for Na⁺ (Figure 22-3). This mechanism of potassium secretion is more likely to occur in the presence of alkalemia when H⁺ is scarce; this is the reason alkalemia tends to cause K⁺ depletion (hypokalemia).

Figure 22-2 Na⁺ reabsorption through secondary active secretion of H⁺. Through the countertransport process, Na⁺ is reabsorbed with HCO3− rather than Cl⁻. This increases the blood’s HCO3− concentration. This process plays a more predominant role in Na⁺ reabsorption when the Cl⁻ ion concentration is low.

Figure 22-3 Na⁺ reabsorption through secondary active secretion of K⁺. This mechanism of Na⁺ reabsorption is most likely to occur in the presence of alkalemia when the H⁺ ion is unavailable for exchange with Na⁺. Alkalemia tends to cause hypokalemia.

Normally, a relatively small amount of the total Na⁺ reabsorption occurs by way of active H⁺ and K⁺ secretion mechanisms. In H⁺ and K⁺ secretion, HCO₃⁻ ion rather than Cl⁻ ion is reabsorbed into the blood with Na⁺. Cl⁻ ion shortage (as may occur with diuretic therapy) increases the demand for H⁺ and K⁺ secretion as a mechanism for reabsorbing sodium.

Secondary Active Transport of Chloride

In most of the tubular segments, Cl⁻ ions are reabsorbed with Na⁺ ions by passive diffusion as described earlier. In the thick segment of the loop of Henle, Cl⁻ ions are transported in a secondary active transport process also known as cotransport. In this mechanism, the same carrier protein referred to previously that combines with Na⁺ in the luminal tubular membrane simultaneously combines with Cl⁻. As Na⁺ diffuses down its electrochemical gradient into the tubule cell, it pulls Cl⁻ with it. This secondary active transport of Cl⁻ requires no ATP energy source; it simply uses the force of the Na⁺ ions’ “downhill” diffusion into the cell to energize the process. In addition to Cl⁻, a significant amount of K⁺ is reabsorbed with Na⁺ through the same mechanism; for each Na⁺ ion, two Cl⁻ ions and one K⁺ ion are cotransported by a membrane carrier protein known as the 1 sodium, 2 chloride, 1 potassium cotransporter.¹

Potassium Regulation

Precise control of extracellular [K⁺] is extremely important because cardiac muscle cells are very sensitive to slight concentration changes; an elevation of only 3 to 4 mEq/L in the plasma [K⁺] can cause lethal arrhythmias.¹ The maintenance of K⁺ balance depends mainly on renal excretion, which must adapt quickly to large variations in K⁺ intake to prevent lethal hyperkalemia. Because more than 98% of total body K⁺ is in the cells, the intracellular compartment is a K⁺ reservoir in hyperkalemia and a source of K⁺ in hypokalemia; redistribution of K⁺ between intracellular and extracellular fluid compartments is an important part of controlling extracellular K⁺ levels.¹ After a normal meal, a person’s K⁺ level would increase to lethal levels if most of the K⁺ did not rapidly move to the intracellular

CLINICAL FOCUS 22-1 Effect of Hypochloremia on Acid-Base Status and Potassium Balance

A woman with chronic congestive heart failure is hospitalized in the intensive care unit. She is receiving diuretic drugs, has a nasogastric suction tube in place, and has been on a low-salt diet before hospitalization. Her arterial blood gas results reveal the following acid-base status:

pH=7.51

PaCO2=43mmHg

HCO3−=33mEq/L

Her plasma electrolyte results are as follows:

	Measured	Normal Range
Na⁺	140 mEq/L	137-147 mEq/L
K⁺	3.0 mEq/L	3.5-4.8 mEq/L
Cl⁻	89 mEq/L	98-105 mEq/L
CO₂	34 mEq/L	25-33 mEq/L

What are the mechanisms contributing to this patient’s metabolic alkalosis?

Discussion

Diuretic drugs, nasogastric suction (removal of gastric HCl), and low-salt diets contribute to hypochloremia. (Note the low Cl⁻ concentration.) Hypochloremia places a greater demand than normal on the secondary active H⁺ and K⁺ secretion mechanisms for Na⁺ reabsorption. Consequently, greater than normal amounts of H⁺ and K⁺ are secreted into the tubular fluid in exchange for Na⁺. This process rids the body of H⁺ and K⁺, while adding HCO3− every time Na⁺ is reabsorbed; this explains the patient’s metabolic alkalosis and hypokalemia. It also helps explain the reciprocal relationship between Cl⁻ and HCO3− concentrations. Low [Cl⁻] leads to increased HCO3− reabsorption with Na⁺ ions. Hypochloremia may cause metabolic alkalosis and hypokalemia. As long as the Cl⁻ ion remains scarce in the tubular filtrate, HCO3− continues to be reabsorbed with Na⁺, and the alkalosis continues. Infusion of a KCl solution is needed to correct this alkalosis by supplying the necessary Cl⁻ for Na⁺ reabsorption. This allows HCO3− diuresis to occur and simultaneously corrects the hypokalemia.

compartment. K⁺ uptake by the cells, and thus its lowered concentration in extracellular fluid, is stimulated by insulin, aldosterone, and beta-adrenergic drugs, all of which activate the Na⁺,K⁺-ATPase pump present in all cell membranes.¹ For this reason, albuterol (a beta₂ agonist) is sometimes administered to individuals with life-threatening hyperkalemia.

Potassium Reabsorption

About 65% of K⁺ in the filtrate is reabsorbed into the blood by cotransport with Na⁺ and Cl⁻ in the proximal tubules (by way of the 1 sodium, 2 chloride, 1 potassium cotransporter).¹ Anything that blocks Na⁺ reabsorption, such as a loop diuretic, impairs K⁺ (and Cl⁻) reabsorption; overuse of loop diuretics can cause hypokalemia and hypochloremia. Approximately another 25% of the filtrate’s K⁺ is reabsorbed by the same cotransport mechanism in the ascending limb of the loop of Henle. The small amount of K⁺

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